THE DIAGNOSIS AND PROPHYLAXIS OF THE IRON DEFICIENCY ...
THE DIAGNOSIS AND PROPHYLAXIS OF THE IRON DEFICIENCY ...
THE DIAGNOSIS AND PROPHYLAXIS OF THE IRON DEFICIENCY ...
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JURNALUL PEDIATRULUI – Year XIV, Vol. XIV, Nr. 53-54, january-june 2011<br />
<strong>THE</strong> <strong>DIAGNOSIS</strong> <strong>AND</strong> <strong>PROPHYLAXIS</strong> <strong>OF</strong><br />
<strong>THE</strong> <strong>IRON</strong> <strong>DEFICIENCY</strong> <strong>AND</strong> <strong>IRON</strong> <strong>DEFICIENCY</strong><br />
ANEMIA IN BABIES <strong>AND</strong> SMALL CHILDREN<br />
Carmen Elena Niculescu¹, Ileana Puiu¹, Laura Marinău¹, D Niculescu², Eleonora Iordache¹<br />
Abstract<br />
The work refers to the diagnosis and prophylaxis of the<br />
iron deficiency and iron deficiency anemia in babies<br />
(naturally or artificially fed) and the children younger than 3<br />
years. The recent studies show that iron deficiency anemia<br />
and iron deficiency without iron deficiency can have long<br />
term effects on neurological development. We hereby<br />
present the adequate iron addition and the screening of iron<br />
deficiency anemia.<br />
Key words: iron deficiency, iron deficiency anemia, baby,<br />
small child, iron addition<br />
Introduction<br />
The iron deficiency and iron deficiency anemia<br />
continue to be a world health issue in the developing nations<br />
and even in the industrialized ones (2,23,28). Nevertheless,<br />
even more important than anemia is the iron deficiency<br />
without anemia which can have long term effects on the<br />
neurological development and behavior, some of them<br />
irreversible. This work refers to the diagnosis and<br />
prophylaxis of iron deficiency anemia.<br />
Definition, prevalence and necessary iron<br />
Anemia is defined as the drop in concentration of the<br />
hemoglobin under 11g/dL in children aged between 12 and<br />
36 months. In certain populations (such as the ones leaving<br />
at high altitudes) the value adjustment must be done.<br />
The normal iron concentration is the situation in which<br />
there is enough iron to maintain the physiological functions<br />
within normal limits. The iron deficiency is the situation in<br />
which there is not enough iron to maintain the physiological<br />
functions within normal limits. The iron deficiency is the<br />
result of the inadequate absorption of iron reported to the<br />
needs or of the negative balance of iron on long term. Each<br />
of these situations leads to the decrease in the iron deposits<br />
measured in serum ferritin or in the iron concentration in the<br />
bone marrow. The iron deficiency may or may not be<br />
accompanied by iron deficiency anemia. The iron deficiency<br />
anemia is the anemia resulting from the iron deficiency<br />
(2,16,18).<br />
The iron overload is the excessive accumulation of iron<br />
in the tissues. The iron overload is usually the result of the<br />
genetic predisposition to excessively absorb and store iron<br />
(e.g. hereditary hemochromatosis). The iron overload may<br />
also be a complication in other hematologic diseases that<br />
need repeated blood transfusions, repeated iron injections or<br />
excessive iron ingestion.<br />
The recommended iron diet is the average of the daily<br />
iron needs that is enough for almost all individuals, based on<br />
age and gender. The adequate iron need is the term used<br />
when there is not enough information to establish the<br />
recommended diet for certain population segments<br />
(newborns, babies younger than 6 months)<br />
80% if the iron quantity of the new born at birth is<br />
formed during the last pregnancy trimester. The premature<br />
newborn “skips” this period and has an iron deficiency.<br />
Certain diseases of the mother, such as anemia, sugar<br />
diabetes, arterial hypertension with in-uterus growth<br />
deficiency, can lead to low iron deposits in the newborns<br />
born on time, as well as the premature ones. The iron<br />
deficiency in premature babies increases with the decrease<br />
of the gestational age and is worsened by the frequent<br />
phlebotomies without adequate blood replacement. On the<br />
other hand the premature babies who receive multiple blood<br />
transfusions run the risk of iron overload. The varying status<br />
in blood in premature babies, with the risk of iron deficiency<br />
or toxicity, makes the determination of the exact needs<br />
impossible, which is estimated at 2-4 mg/day if administered<br />
orally (1,12,28).<br />
IOM (Institute of Medicine), taking into account the<br />
average iron content of the human milk, has determined the<br />
adequate intake at 0.27 mg/day in full term newborns since<br />
birth until 6 months of age (16).<br />
The average of the iron content of the human milk if<br />
0.37 mg/L and the average of the milk needs of the<br />
exclusively fed baby is estimated at 0.78 L/day. From these<br />
valued the necessary amount has been determined at 0.27<br />
mg/day for the full term newborn until 6 months of age.<br />
IOM has considered that there must be a direct connection<br />
between the age of the baby and the milk ingestion; thus<br />
there must not be any correlation based on weight.<br />
Nevertheless, there is a large variation in the iron<br />
concentration in human milk and there is no guarantee that it<br />
will cover the needs of the baby. For the babies between 6<br />
and 12 months the recommended diet for iron (according to<br />
IOM) is of 11 mg/day (16).<br />
¹Pediatric Department, University of Medicine and Pharmacy Craiova<br />
²Orthopedy and Traumatology Department, University of Medicine and Pharmacy Craiova<br />
E-mail: niculescudragos@yahoo.com, vipuiu@yahoo.com, marinau_doru@yahoo.co.uk, niculescudragos@yahoo.com,<br />
eleonora_iordache2@yahoo.com<br />
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JURNALUL PEDIATRULUI – Year XIV, Vol. XIV, Nr. 53-54, january-june 2011<br />
The amount of iron losses – the epithelial exfoliation of<br />
the skin, the urinary and digestive tracts – was added to the<br />
amount of the iron needs for the increase of the blood<br />
volume with the growth of tissue mass and to the iron<br />
deposits of that period. It is mentioned that the necessary<br />
iron in babies does not pass directly from 0.27 mg/day to 11<br />
mg/day at the age of 6 months. It is obvious that the full<br />
term healthy newborn needs very little iron in the first 6<br />
months as compared to the needs after 6 months (16,25).<br />
Using the same reasoning, IOM considers that that<br />
recommended necessary iron for the child aged 1-3 is of 7<br />
mg/day.<br />
There is no national statistic on the prevalence of iron<br />
deficiency and iron deficiency anemia in babies. The general<br />
prevalence in the USA of iron deficiency anemia has<br />
dropped in babies and small children since the 1970s, with<br />
the use of iron-enriched milk formulae and with the drop of<br />
the use of cow milk in babies (2). Related the iron<br />
deficiency anemia is the issue of the interaction between<br />
iron and led. If the studies made on animals and humans it<br />
has been noticed that the iron deficiency anemia increases<br />
the intestinal absorption of led. Thus, iron deficiency anemia<br />
decreases the efficiency of lead chelators and the iron<br />
supplements correct this issue (7,38).<br />
Many studies have shown the connection between iron<br />
deficiency anemia and later cognitive deficiencies. Lozoff et<br />
colab. (2006) have shown the cognitive deficiencies in the<br />
1-2 decades after iron deficiency during the baby stage (18).<br />
Nevertheless, it is difficult to determine a causality<br />
connection. It is known that iron is essential in neurological<br />
development. The iron deficiency affects the neuronal<br />
metabolism, the neurotransmitter metabolism, the<br />
mielinisition and memory (6,11,30). These observations<br />
could explain the behavioral problems in children with iron<br />
deficiency.<br />
Paraclinical diagnosis<br />
We follow certain parameters: the hemoglobin<br />
concentration, the reticulocites, erythrocitary indexes, the<br />
total iron assimilation, the transferrine saturation,<br />
protoporphyrine, ferritine and sTfr (transferrine receptor).<br />
The last parameter, the soluble form of the transferrine<br />
receptor that freely travels into the plasma, is an important<br />
indicator of the status of iron in the organism.<br />
In this table we show the changed in the main<br />
parameters.<br />
Parameter<br />
Iron deficiency without Iron deficiency anemia Iron overload<br />
anemia<br />
Ferritine ↓ ↓↓ ↑<br />
Transferrine saturation ↓ ↓ ↑↑<br />
Transferrine receptor ↑↑ ↑↑↑ ↓<br />
(sTfr)<br />
Reticulocitary hemoglobin ↓ ↓ Normal<br />
Hemoglobin normal ↓ Normal<br />
VEM normal ↓ normal<br />
↓ low value, ↑ high value<br />
The iron status in children is not determined by a simple<br />
determination of hemoglobin concentration. The decrease in<br />
hemoglobin can have a variety of causes, of which we<br />
mention the hemolitical anemia, the chronic disease anemia,<br />
the B12 or folic acid deficiency anemia, the genetic disease<br />
anemia. But once put the iron deficiency diagnosis, the<br />
supervision of the hemoglobin concentration is a good<br />
response measure to the treatment.<br />
Any set of analysis will include the hemoglobin<br />
concentration to determine whether or not there is anemia.<br />
The three parameters giving selective data about the status<br />
of the iron are: ferritine, reticulocitary hemoglobin and the<br />
transferrine receptor.<br />
Ferritine is a sensitive parameter for the assessment of<br />
the iron deposits in healthy subjects (1 µg/L of ferritine<br />
corresponds to 8-10 mg of available iron). In children the<br />
value showing the depletion of the iron deposits is of 10<br />
µg/L (in adults 12 µg/L) (9,17). Because the serum ferritine<br />
is a short phase reactant, its concentration can be increased<br />
in the presence of chronic inflammations, infections,<br />
malignancies, hepatic diseases. A simultaneous<br />
determination of protein C reactive is needed to exclude the<br />
inflammation.<br />
Even though serum ferritine has a lower accuracy that<br />
reticulocitary hemoglobin or the transferrine recepton, the<br />
combination of ferritine and protein C reactive is more<br />
accessible and a more reliable test as long as the protein C<br />
reactive is not high (9,17,34).<br />
The reticulocitary hemoglobin and the transferrine<br />
receptor are not influenced by the inflammation,<br />
malignancy, infections, chronic diseases and are preferable<br />
for the diagnosis. The reticulocitary hemoglobin has been<br />
validated, standardized in children and actually available.<br />
This parameter provides a measurement of the available iron<br />
in the cells recently released by the bone marrow (5). The<br />
reticulocitary hemoglobin can be measured by citometric<br />
flow and the low concentration is the most important in<br />
predicting iron deficiency in children.<br />
The transferrine receptor (sTfr) is a measure of the iron<br />
status which finds the iron deficiency on a cellular level<br />
(32,37). It is found on the cell membrane and allows the<br />
transfer of iron in the cell. When the iron is insufficient,<br />
there is an imbalance of the transferrine receptor’s<br />
permission for the cell to have a more efficient iron<br />
composition and later its circular form has a serum increase.<br />
An increase in serum in the transferine receptor can be<br />
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JURNALUL PEDIATRULUI – Year XIV, Vol. XIV, Nr. 53-54, january-june 2011<br />
found in the patients with iron deficiency or iron deficiency<br />
anemia, even though the serum doesn’t increase until the<br />
iron deposits are depleted in the adults. The assessment of<br />
the transferrine receptor is not usually available and the<br />
standard value for children has not yet been established.<br />
For putting the diagnosis of iron deficiency anemia<br />
(when a hemoglobin value smaller than 11g/dl is<br />
associated), nowadays the following tests can be used:<br />
ferritine + protein C reactive or reticulocitary hemoglobin.<br />
For the iron deficiency diagnosis without anemia the same<br />
parameters are measured.<br />
Another approach in the diagnosis of iron deficiency<br />
anemia in mild anemia children (Hb 10-11g/dL) is the<br />
monitoring of the response to iron supplements, especially if<br />
the history of the nutrition involves an iron-poor diet. An<br />
increase in hemoglobin of 1 g/dL after 1 months of<br />
treatment is used as positive for iron deficiency anemia.<br />
This approach imposes an adequate iron treatment, the<br />
compliance of the patient and an adequate absorption.<br />
Correcting the iron deficiency and iron deficiency anemia.<br />
Premature babies. The naturally-fed premature babies<br />
(below 37 weeks of gestational age) will receive elementary<br />
iron supplements of 2 mg/kg/day beginning with 1 month of<br />
age until 12 months. The iron can be provided through<br />
medication or through an iron-rich diet. The premature<br />
babies who are fed with formulae for premature babies (14.6<br />
mg iron/L) or ordinary formulae (12 mg iron/L) will receive<br />
approximately 1.8-2.2 mg/kg/day assuming a milk<br />
consumption of 150 ml/kg/day (12,29).<br />
Despite the iron-enriched formulae, 14% of premature<br />
babies have an iron deficiency between 4 and 8 months of<br />
age. Thus the enriched formulae need an iron supplement<br />
addition. The exception for these iron supplements are the<br />
premature babies who received multiple transfusions during<br />
the hospitalization period, who might not need iron<br />
supplements.<br />
Naturally fed full term babies. The full term baby has a<br />
higher hemoglobin concentration and a higher blood volume<br />
as compared to body weight. They go through a<br />
physiological decrease in hemoglobin and blood volume<br />
during the first four months of life. Usually the iron deposits<br />
are enough for the first 4-6 months. The iron content of<br />
human milk is enough for the newborns who are exclusively<br />
naturally fed.<br />
The exclusively natural diet is recommended for 6<br />
months. The exclusively natural diet for the newborns after<br />
6 months is connected to a higher risk of iron deficiency<br />
anemia at the age of 9 months. The recommendation for an<br />
exclusively natural diet does not take into account the babies<br />
born with low iron deposits (the newborns with a low<br />
weight at birth, the babies whose mothers have diabetes), a<br />
situation which also determines a low iron concentration at<br />
the age of 9 months.<br />
It is recommended that the full term babies who are<br />
exclusively naturally fed receive an iron supplement of 1<br />
mg/kg/day starting with the age of 4 months until the<br />
introduction of the iron-rich foods (10,25).<br />
For the mixed-fed babies, the proportion of the breastfeeding<br />
as opposed to the formulae is uncertain. Thus, after<br />
4 months the babies who do not receive an iron-rich diet will<br />
get 1 mg/kgc/day supplemental iron.<br />
Artificially fed full term babies. The American Pediatric<br />
Association has concluded that the milk formulae containing<br />
12 mg elemental iron /L are safe (26,27,31). There is not<br />
enough data to relate the formulae with 12 mg/L to the<br />
gastro-intestinal symptoms (3,12,31).<br />
Small children (1-3 years). The necessary iron in small<br />
children is of 7 mg/day. Ideally, the necessary iron must be<br />
provided through food naturally rich in iron and vitamin C<br />
which stimulates the iron absorption. In the developing<br />
countries, the necessary iron is covered by the iron<br />
strengthening of certain foods such as corn flour, soy sauce,<br />
rice, cereal. Nevertheless, there are barriers to providing an<br />
optimal iron intake: the lack of education of the parents, the<br />
low compliance to any digestive adverse effects, the price of<br />
enriched products, the federal nutrition programs which do<br />
not provide iron supplements. In the US, the iron-enriching<br />
of formulae and cereals for the babies has lead to the<br />
decrease of iron deficiency anemia (2).<br />
As an alternative for those who do not take enough iron<br />
from the diet, there are also the iron supplements which are<br />
available as a component of the multivitamin syrup or<br />
chewable tablets (4,13,14).<br />
Screening for iron deficiency and iron deficiency anemia.<br />
The universal screening must assess the risk factors<br />
associated to the iron deficiency/iron deficiency anemia: a<br />
history of premature birth or small weight at birth, exposure<br />
to led, an exclusively natural diet over 4 months without<br />
iron supplements, an integral milk diet, a diet of non-iron<br />
enriched cereal or of low-iron foods. The additional risk<br />
factors include nutrition problems, an inadequate diet, a<br />
stationary weight curve.<br />
In the US 60% of the anemia cases are not due to the<br />
iron deficiency and most of the iron deficiency children do<br />
not have anemia.<br />
Selective screening tests can be done at any age when<br />
the risk factors for iron deficiency and iron deficiency<br />
anemia are found.<br />
After determining the hemoglobin concentration, in<br />
children with hemoglobin below 11 mg/dL or with a high<br />
risk of iron deficiency the ferritine + protein C reactive and<br />
reticulocitary hemoglobin are determined. The<br />
determination of the transferrine receptor will enter the<br />
screening tests once the value in children is determined.<br />
Conclusions<br />
It is important that we eliminate the iron deficiency and<br />
iron deficiency anemia in babies and young children,<br />
considering their impact on cognitive and behavioral<br />
development(22,24,30). There are controversies regarding<br />
the time and methods of screening and on the use of iron<br />
supplements.<br />
The present data support the following<br />
recommendations:<br />
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JURNALUL PEDIATRULUI – Year XIV, Vol. XIV, Nr. 53-54, january-june 2011<br />
• Healthy newborns born on time have enough iron for at<br />
least the first four months of life. The exclusively natural<br />
feeding after the first four months without iron supplements<br />
leads to an iron deficiency. The naturally fed babies must<br />
receive 1 mg/kg/day starting with the age of 4 months until<br />
the iron-rich foods (including cereal) are introduced in the<br />
diet.<br />
• For the mixed-fed babies, the proportion of mother milk<br />
vs. formula is uncertain. Consequently, starting with the age<br />
of 4 months the mixed-fed babies who do not receive ironrich<br />
foods must receive 1 mg elemental iron/kg/day.<br />
• For the formulae-fed babies, the necessary iron can be<br />
covered by standard milk formulae (iron content 10-12<br />
mg/L) and the introduction of foods containing iron after 4-6<br />
months of age, including cereal. The integral milk must not<br />
be used before 1 year of age.<br />
• The iron addition between 6 and 12 months must be of 11<br />
mg/day. When the food becomes more varied, the<br />
vegetables and red meat with a high iron content are<br />
introduced. If the food does not cover the necessary, the<br />
liquid iron supplements will be introduced.<br />
• The small child (1-3 years) has a necessary of iron of 7<br />
mg/day which will be provided by the red meat, ironenriched<br />
cereal, iron-rich vegetables, fruit with vitamin C<br />
which increases the iron absorption (35,36). In the case of<br />
the children who do not receive the appropriate iron-rich<br />
food, iron supplements are recommended as syrup or<br />
chewing tablets.<br />
• Premature babies must receive an iron addition of at least 2<br />
mg/kg/day until 12 months old, including the supplementary<br />
iron in the milk formulae. Naturally fed premature babies<br />
must receive iron supplements of 2 mg/kg/day after 1<br />
months of age until the diversifying with iron-rich foods<br />
(29). The exception consists of the premature babies who<br />
have received iron through blood transfusions and<br />
erythrocitary mass transfusions.<br />
• The universal anemia screening must be done at<br />
approximately 12 months with the determination of the<br />
hemoglobin concentration and the assessment of the risk<br />
factors related to the iron deficiency/ iron deficiency<br />
anemia. These risk factors include precarious socioeconomic<br />
status, a history of premature birth or small<br />
weight at birth, exposure to led, exclusively natural nutrition<br />
until 4 months of age without iron supplements, iron-rich<br />
foods and iron-enriched cereal. Additional risk factors are<br />
the eating disorders, inadequate weight gain, inadequate<br />
nutrition. In the case of babies and small children, the<br />
screening must be done whenever the risk factors are<br />
involved.<br />
• If the hemoglobin level is less than 11 mg/dL at 12 months<br />
the cause of the anemia will be investigated. If there are risk<br />
factors of iron deficiency the status of the iron will be<br />
investigated. The ferritin + reactive protein C and<br />
reticulocitary hemoglobin will be determined. Afterwards<br />
the correct treatment will be applied.<br />
• If a child has mild anemia (Hb 10-11 mg/dL) and can be<br />
closely monitored, an alternative diagnosis method will be<br />
the increase by 1g/dl of the hemoglobin concentration after a<br />
month of iron therapy.<br />
• The use of the transferrin receptor (sTfs) as screening<br />
for the iron deficiency is promising and the establishing of<br />
the standard value is expected for the use on babies and<br />
small children.<br />
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Petru Rares Street, No. 3,<br />
Craiova, Romania<br />
E-mail: niculescudragos@yahoo.com<br />
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